Therapeutic composition containing aluminum proteinate



TI-ERAPEU'I'IC CGMPQSITIQN CONTAINING ALUMINUM PROTEINATE No Drawing.Application December 13, 1955 Serial No. 552,705

5 Qlaims. (Cl. 16755) This invention relates to improved therapeuticcompositions and, more particularly, to compositions having increasedstability and enhanced therapeutic acceptance.

It is well known that certain drugs or therapeutic agents aresusceptible to deterioration in the presence of moisture. When suchmaterials are compounded in the form of powder or tablets and storedprior to use, care must be taken to exclude moisture therefrom in orderto prevent hydrolytic decomposition. A sack of silica gel may bepackaged with medicinal agents which are particularly sensitive tomoisture to act as a desiccant in the container. Since this drying agentcannot be ingested, its admixture with drugs during compounding to actas an internal desiccant is not possible. Furthermore, when certaindrugs are taken in tablet form, they have a tendency to induceundesirable acid conditions in the stomach. Compounds that have beenproposed for use with drugs to combat the undesired acid condition havenot been entirely satisfactory, since they may promote breakdown of theactive components.

Accordingly, it is an object of the present invention to provide meansfor stabilizing medicinal agents which are themselves subject tohydrolytic decomposition.

It is another object of this invention to provide, with therapeuticcompositions containing a drug or agent having inherently acidic andirritating properties, a compound which counteracts such properties.

It is another object of the invention to provide a sub stance for theremoval of free hydrochloric acid in admixture with therapeutic agentswhich may promote gastric hyperacidity.

it is a further object of this invention to provide in combination withanticholinergic agents a substance which will function to give rapidrelief by taking up free hydrochloric acid already present in thestomach.

It is a further object of the invention to provide in combination withan autihistaminic agent a substance which functions to relieve gastrichyperacidity possibly resulting from the high istamine levels of theblood as associated with allergic conditions.

Further and additional objects will appear from the followingdescription and the accompanying claims.

In accordance with this invention, a therapeutic composition has beenprovided which has added thereto an aluminum proteinate and theinvention is particularly useful in the preparation of tabletedproducts, such as the salicylates, the antihistamines and theanticholinergics. The aluminum proteinate in such tableted compositionsis added in dry form to the compounded mixture just before tableting. Itserves the dual purpose of an internal desiccant to remove residualmoisture and to act as a buifering agent to prevent or relieveconditions of hyperacidity when the tablet is taken by the patient.Aluminum proteinates particularly suitable for the purposes of thisinvention may be prepared as described in my 00- pending patentapplications Serial No. 249,817, filed October l, 1951, now U.S. PatentNo. 2,721,861, and Serial No. 412,085, filed February 23, 1954. Suchaluminum proteinates are, generally speaking, unique complexes of asemi-hydrate of aluminum with the protein.

atcnt In the dry state they are free-flowing powders having ex cellentdehydrating and acid-combining properties. 7

Aluminum proteinates, upon drying, assume a solid gel structure,apparently containing randomly intertwined strands of cross-linkedprotein molecules. It has been found that these materials act much inthe manner of silica gel in their ability to adsorb and retain moisture.To demonstrate the moisture adsorption properties of aluminumproteinate, an aluminum milk proteinate was exposed to varying relativehumidities in constant humidity chambers. The following Table I comparesalu minum milk proteinate with other pharmaceutical components asmoisture adsorbents under various humidity conditions. Silica gel isalso included for the purposes of comparison, since it is commonpractice to use this material in a separate package to remove moisturefrom enclosed areas.

It will be apparent that, of the various antacids listed in Table 1,aluminum milk proteinate and magnesium trisilicate show superiorproperties as moisture adsorbents. Magnesium trisilicate, however, is soinherently alkaline that it may promote decomposition of certain drugs,and for this reason is not usually recommended as an internal desiccantfor medicinal mixtures.

Thus, in accordance with this invention, it has been found that theaddition of a dried aluminum proteinate to a powdered or granulatedtherapeutic mixture serves to adsorb residual moisture and haltdeterioration. So elfective is aluminum proteinate in contact withmedicinal agents containing free or bound water that hydrolyticdecomposition of these drugs during storage becomes negligible. Inasmuchas the protein in the aluminum proteinate is edible, such aluminumproteinates have the advantage over silica gel in that the proteinate ispharmaceutically acceptable as a component of oral medicaments. Being abuflering agent, aluminum proteinate also acts to remove simultaneouslywith the water any free basic or acidic ions.

Aluminum proteinate has the funther advantage in combination with drugsof being rapidly solubilized in the gastric juice to release the activecomponents. Since aluminum proteinate functions to bind free acid, ittends to counteract irritation caused by inherently acidic or basicdrugs. It also functions to combat gastric hyperacidity and is adesirable adjunct with drugs promoting this condition. When administeredin combination with other drugs which reduce gastric acidity by meansother than the absorption of hydrochloric acid, the aluminum proteinatepromotes rapid relief by taking up any free acid already present in thestomach. In conjunction with other groups of medicaments used primarilyto treat conditions other than hyperacidity but which condition may havean accompanying incidental hyperacidity, aluminum proteinate functionsto counteract gastric distress.

Salicylic acid and salicylic acid derivatives are widely used asanalgesics and antipyretics. These drugs are prescribed routinely forinflammatory processes associated with rheumatic, rheumatoid andarthritic syndromes. Acetyl salicylic acid has particular merit as apain killer, due to its low toxicity and nonnarcotic nature.

Salicylic acid, usually prescribed in the form of its sodium salt, isfairly stable if protected from the action of light. However, wheningested into the acid environment of the stomach, it may become aserious mucosal irritant. It is common practice to provide an entericcoating for this drug so that release of the active component takesplace in the more alkaline intestines. Attempts to apply enteric coatingconsistently solubilized in the in testinal area have been notoriouslyunsuccessful. In ac cordance with this invention combinations ofaluminum proteinate with salicylic acid or its sodium salt serve toreduce gastric acidity and permit the rapid absorption of the salicylicacid from the gastric area without nausea.

Acetyl salicylic acid is subject to hydrolytic decomposition in thepresence of moisture. The acetic and salicylic acid ions so formedcatalyze further decomposition. Acetyl salicylic acid is commonlyprescribed in combination with other drugs such as acetopheuetidine,acetanilide, antipyrene, etc. Unless special precautions are taken toexclude moisture during compounding of these mixtures, the rate ofhydrolysis may become very rapid. It has now been found in accordancewith this invention that an aluminum proteinate may be intimatelyadmixed with acetyl salicylic acid alone or in combination with otherdrugs to provide an environment which effectively prevents hydrolyticfission during compounding, tableting and storage of this medicinalagent. Acetyl salicylic acid may also give rise to gastric distress dueto its inherently acid nature and the presence of the aluminumproteinate also bulfers to counteract such irritation.

Stability studies on acetyl salicylic acid in combination with aluminumproteinate were conducted at 45 C. for a period of one year. At thistemperature, control samples of acetyl salicylic acid showedconsiderable hydrolysis as indicated by the release of free acetic andsalicylic acids at the end of two months. It will be noted from Table IIthat the inclusion of -15% aluminum proteinate in a dry mixture or intablets effectively prevents hydrolysis. For comparative purposes,tablets containing equivalent amounts of other antacid materials werestudied under similar conditions.

TABLE II Stability of acetyl salicylic acid in combination with variousantacids Temperature: 45 C. I Analysis conducted by U.S.P. test for freesalicylic acid 111 acetyl salicylic acid. Control materiel assayed attime samples prepared showed 0.08% free salicylic acid.

Of the antacid materials listed, aluminum milk proteinate offeredmaximum protection against hydrolytic decomposition. It might beexpected that aluminum hydroxide and aluminum glycinate would offerbetter protection against hydrolysis due to inactivation of free aceticacid but apparently moisture levels were not held sufiiciently low toafford protection. Magnesium trisilicate and calcium carbonate aresufiiciently basic to catalyze the breakdown of acetyl salicylic acid.

For a more complete understanding of this invention reference will nowbe made to several specific examples of compositions prepared inaccordance therewith; however, it will be appreciated that the inventionis not to be limited to the details of the examples given.

EXAMPLE 1 Pounds Acetyl salicylic acid (40 mesh) 5 Aluminum milkproteinate 0.75 Sterotex 0.05

These materials were dry mixed and directly compressed into 5.8 gr.tablets.

EXAMPLE 2 Acetyl salicylic acid (40 mesh) lbs 35 Phenacetin lbs 25Caffeine lbs 5 Aluminum caseinate lbs 4 Sterotex oz 6 The phenacetin andcafieine were mixed and granulated using isopropyl alcohol. Afterdrying, this granulation was mixed well with the acetyl salicylic acidand the aluminum caseinate. After the addition of the lubricantSterotex, tablets were directly compressed.

EXAMPLE 3 Sodium salicylate lbs 10 Aluminum soya proteinate lbs 1.5Sterotex oz 2 The sodium salicylate and aluminum soya proteinate wereintimately mixed, the Sterotex added and 6.5 gr. tablets directlycompressed.

EXAMPLE 4 Pounds Sodium chloride a 10 Aluminum milk proteinate 2 Thesetwo components were dry mixed and compressed into 12 gr. tablets.Aluminum proteinate assists in counteracting gastric hyperexcretion ofhydrochloric acid due to high concentrations of salt.

EXAMPLE 5 Methantheline bromide (,B-diethylaminoethyl-9-xanthenecarboxylate methobromide) gm 250 Aluminum milk proteinate lbs 5 Sterotexn7 1 The above components were dry mixed and directly compressed toprovide tablets containing 50 milligrams of the anticholinergic agentand 7 gr. of aluminum milk The above components were dry mixed andtable-ted to provide 25 milligrams of the antihistaminic agent and 7 gr.of aluminum milk proteinate. The aluminum proteinate serves to allaygastric hyperacidity which is often associated with allergic conditionsdue to the high histamine levels of the blood.

In the foregoing examples, the Sterotex, a stearic acid compound, servesas a mold lubricant in the tableting operation, as is well known.

It as been diflicult to assign an exact chemical structure to aluminumproteinate. Some water of hydration is retained in the dried product,but this amount is substantially lower than that found in dried aluminumhydroxide gels. Typical analyses on aluminum proteinates prepared fromprotein of difierent origin show about 4446% protein and about 20-22%aluminum calculated as aluminum oxide. Variations in such analysesresult from the use of different proteins and varying percentages ofbound water. Aluminum proteinates satisfactory for the purposes of thisinvention may be prepared using skim milk, casein, soya protein,gelatin, blood protein or other edible protein material which may bedissolved or colloidally dispersed. It can be realized that aluminumhydroxide gel may be admixed with aluminum proteinate before or afterdrying to impart higher acid combining properties to the resultantproduct. It has been found that aluminum proteinate which has beenexposed to high humidities may be regenerated by heating at 80 C. forone hour. Such regenerated aluminum proteinate does not lose its abilityto adsorb moisture nor its complete solubility in 0.1 N hydrochloricacid.

In the foregoing examples are indicated a few specific drugs ortherapeutic compositions with which the aluminum proteinate may beincorporated in accordance with the teachings of this invention.However, it will be apparent that others may also be used and thespecific proportions of the ingredients may vary widely. The amount ofaluminum proteinate used will depend upon many factors including thedesiccating capacity and bufiering capacity desired in the finalproduct. Usually the amount of aluminimum proteinate will constitute atleast 5 percent by weight of the composition and preferably at least 10percent by weight. The tablets prepared in accordance with theseexamples were exceedingly stable upon storage because of the internaldesiccating properties of the aluminum proteinate and when ingested thealuminum proteinate acted as a buifer for the purposes above set forth.

While several particular embodiments of this invention are shown above,it will be understood, of course, that the invention is not to belimited thereto, since many modifications may be made, and it iscontemplated, therefore, by the appended claims, to cover any suchmodifications as fall Within the true spirit and scope of thisinvention.

I claim:

1. A composition comprising an aluminum proteinate wherein the proteinof said proteinate is selected from the group consisting of milkprotein, casein, soya protein, gelatin and blood protein and atherapeutic agent selected from the group consisting of salicylic acid,sodium salicylate, acetyl salicylic acid, fl-diethylaminoethyl-9-xanthene carboxylate methobromide and 2-(benzhydryloxy)-N,N-dimethylamine hydrochloride.

2. The composition recited in claim 1 wherein said protein is a milkprotein.

3. The composition recited in claim 1 wherein said therapeutic agent isacetyl salicylic acid.

4. A composition comprising an aluminum milk proteinate and acetylsalicylic acid.

5. A composition of matter in the form of a compressed tablet whichcomprises acetyl salicylic acid and at least about 5 percent by weightof an aluminum milk proteinate.

References Cited in the file of this patent UNITED STATES PATENTSPaterson Oct. 25, 1955

1. A COMPOSITION COMPRISING AN ALUMINUM PROTEINATE WHEREIN THE PROTEINOF SAID PROTEINATE IS SELECTED FROM THE GROUP CONSISTING OF MILKPROTEIN, CASEIN, SOYA PROTEIN, GELATIN AND BLOOD PROTEIN AND ATHERAPEUTIC AGENT SELECTED FROM THE GROUP CONSISTING OF SALICYLIC ACID,SODIUM ALICYLATE, ACETYL SALICYLIC ACID, B-DIETHYLAMINOETHYL-9XANTHENECARBOXYLATE METHOBROMIDE AND 2-(BENZHYDRYLOXY)-N,N-DIMETHYLAMINEHYDROCHORIDE.